ABSTRACT
Bile acids are synthesized in the liver from cholesterol and serve critical physiological functions essential for lipid homeostasis. Disruption of bile acid homeostasis is thought to play a major role in the progression of hepatic steatosis to nonalcoholic steatohepatitis (NASH). NASH is the severe form of nonalcoholic fatty liver disease (NAFLD), characterized by inflammation and fibrosis. Farnesoid X receptor (FXR) is the most important nuclear receptor for maintaining BA homeostasis. FXR plays a tissue-specific role in suppressing BA synthesis and promoting BA enterohepatic circulation. FXR deficiency has been shown to progress and exacerbate NASH development, and FXR activation has been protective against the liver inflammation associated with NASH. In the intestine, FXR activation triggers induction of downstream targets such as FGF-19, which is well-described for its liver fat lowering and otherwise liver protective functions. It has also been demonstrated that alterations of these pathways can lead to an increase of liver inflammation and fibrosis. Synthetic FXR agonists and FGF19 protein may be promising agents to treat NASH, with obeticholic acid (OCA), cilofexor, tropifexor, EDP-305 and aldafermin currently in phase II or III clinical trials of NASH. In this chapter, we summarize the current knowledge of the interaction between bile acids and the development of NASH and novel therapies targeting bile acid synthesis for NASH treatment.
